(Hypertension. 1999;33:402-407.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
The Myocardial ß-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats
Presented in part at the 52nd Annual Fall Conference and Scientific Sessions of the American Heart Association, sponsored by American Heart Association's Council for High Blood Pressure Research, Philadelphia, Pa, September 15–18, 1998.
From the Department of Cardiovascular Pharmacology (K.M.A., R.N.W.), SmithKline Beecham Pharmaceuticals, King of Prussia, Pa; and the Department of Surgery (A.D.E., W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Dr Karen M. Anderson, SmithKline Beecham Pharmaceuticals, PO Box 1539, 709 Swedeland Rd, UW2510, King of Prussia, PA 19406. E-mail Karen_M_Anderson{at}SBPHRD.com
Abstract—Responsiveness to ß-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced ß-adrenergic receptor (ßAR) density, elevated ß-adrenergic receptor kinase 1 (ßARK1) levels, and functional uncoupling of remaining receptors. The temporal nature of changes in the human myocardial ß-adrenergic system relative to onset of symptomatic heart failure (HF) has been difficult to discern. A relatively new model of HF, the spontaneously hypertensive heart failure (SHHF) rat spontaneously and reproducibly develops left ventricular hypertrophy (LVH) and progresses to HF, thus enabling longitudinal studies to examine the cellular and molecular bases for hypertension-induced cardiac hypertrophy and subsequent HF. The purpose of this study was to examine age-dependent changes in the ßAR system in this model. Lean male SHHF rats at 3, 7, 14, and 20 months were compared with age-matched Sprague-Dawley (SD) control rats ([C]; 4 animals/group). At all ages the SHHF rats had elevated blood pressures and left ventricular end-diastolic pressure relative to the SD control rats (P<0.05). Compared with age-matched SD control rats, LVH was evident by 3 months in SHHF rats; 20-month-old SHHF rats had significantly greater LVH compared with the other SHHF rat groups. ß-adrenergic responsiveness (maximal heart rate to isoproterenol) was reduced only in 20-month-old SHHF rats. ßARK1 protein levels and activity were elevated at 14 months (162±10% and 195±20% C, respectively), and ßARK1 protein remained elevated at 20 months (140±14% C). In contrast, G protein–coupled receptor kinase 5, a second receptor kinase in the heart, remained unchanged at all ages. ßAR density did not change with age in the SD control rats and was similar in the SHHF rats until 20 months of age when the receptor number was reduced (30±1%). These data indicate that cardiac dysfunction is coincident with reduced ßAR density. Importantly, cardiac dysfunction was preceded by elevated ßARK1 levels and activity, thus suggesting that ßARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF. Furthermore, these results indicate that the SHHF rat is a powerful model for use in examination of the mechanisms involved in alterations of ß-adrenergic signaling that occur in human HF.
Key Words: hypertension, experimental • hypertrophy, cardiac • heart failure • receptors, adrenergic, beta • kinase • adenylyl cyclase • rats, inbred SHR
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